Asenapine, trademark Saphris®, chemically trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, in sublingual dissolving tablet form, has been approved in US in August 2009 for the acute treatment of adult patients with schizophrenia and as monotherapy for acute mania or mixed episodes associated with bipolar disorders. The FDA has recently approved its use as ongoing maintenance treatment for schizophrenia and as adjunctive therapy with lithium or with valproate for bipolar 1 disorder.
Certain crystalline addition salts of Asenapine, for instance a fumarate (EP 0569096), salts with sulfonic acids (WO 98/54186), and a pamoate or hemipamoate salt (EP 0569096), are described in the literature. The pamoate salt is disclosed to be amorphous and the hemipamoate salt is a mixture of amorphous and crystalline phase, wherein the palmitate is described as oil. The marketed form is the maleate salt, which is disclosed to exist in polymorphic forms (WO 2006/106135). The known Asenapine salts have a low solubility in water. For example, Funke et. al. (Arzneim.-Forsch./Drug Res. 40, 1999, 536-539) reports that a saturated solution of the maleate salt of Asenapine at 23° C. has a concentration of 5.8 mg/ml at pH=4.4 (see also US2008/0306133 A1 regarding the solubility of Asenapine. This translates into a free base solubility of about 4.1 mg/ml, this value is in good agreement with solubility tests that were carried out with Asenapine maleate. WO 2009/135091 also discloses Asenapine and related compounds and salts thereof for treating a neuronal or non-neuronal indication. Peter van Hoof et al. (Amorphous Pharmaceutical Materials, September 2009) describe a method for validation of a drug product of Asenapine in solid state form.
The discovery of new crystalline salts of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example a pharmaceutical dosage form of a drug with targeted release profile or other desired characteristic.
For example, the premise for a sublingual dissolving tablet form is an active ingredient exhibiting good solubility in a fast dissolving matrix.
It is an objective of the invention to provide a pharmaceutically acceptable forms of Asenapine with good solubility.
It is also an object of the invention to provide a form of Asenapine having a good chemical and/or physical stability and/or good processability, both during its preparation and in the preparation of pharmaceutical compositions containing Asenapine.
The problems underlying the invention are solved by the subject matters defined in the claims.
Surprisingly, it was found that crystalline HCl salts of Asenapine as described below may provide beneficial properties e.g. regarding solubility and may furthermore enhance the performance of dosage forms comprising said Asenapine salts. In particular, using hydrochloric acid for preparing Asenapine salts allows providing crystalline salts that may have enhanced properties.
It has additionally, been found in the context of the invention that Asenapine HCl hydrates can be prepared by treating Asenapine HCl salts in anhydrous form with water. Likewise, it is possible to convert Asenapine HCl hydrates into Asenapine HCl anhydrous forms.